Multiple endocrine neoplasia type 2
Encyclopedia
Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma and amyloid producing medullary thyroid carcinoma", "PTC syndrome," and "Sipple syndrome") is a group of medical disorders associated with tumors of the endocrine system
. The tumors may be benign
or malignant (cancer
). They generally occur in endocrine organs (e.g. thyroid
, parathyroid, and adrenals
), but may also occur in endocrine tissues of organs not classically thought of as endocrine.
MEN2 is a sub-type of MEN (multiple endocrine neoplasia
) and itself has sub-types, as discussed below.
A table in the multiple endocrine neoplasia
article compares the various MEN syndromes. MEN2 and MEN1 are distinct conditions, despite their similar names. MEN2 includes MEN2A, MEN2B
and familial medullary thyroid cancer.
The common feature among the three sub-types of MEN2 is a high propensity to develop medullary thyroid carcinoma.
, with characteristic musculoskeletal and/or lip and/or gastrointestinal findings.
Medullary thyroid carcinoma (MTC) represent the most frequent initial diagnosis. Occasionally pheochromocytoma
and primary hyperparathyroidism
may be the initial diagnosis.
In MEN2A primary hyperparathyroidism occurs in only 10%-30% and is usually diagnosed after the third decade of life. It occur in children but this is rare. It may be the sole clinical manifestation of this syndrome but this is unusual.
MEN2A associates medullary thyroid carcinoma with pheochromocytoma in about 20-50% of cases and with primary hyperparathyroidism in 5-20% of cases.
MEN2B associates medullary thyroid carcinoma with pheochromocytoma in 50% of cases, with marfanoid habitus and with mucosal and digestive neurofibromatosis
.
In familial isolated medullary thyroid carcinoma the other components of the disease are absent.
Familial genetic screening is recommended to identify at risk subjects who will develop the disease, permitting early management by performing prophylactic thyroidectomy, giving them the best chance of cure.
Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC indicating the necessity of a complete thyroid surgery for index cases with MTC and the early thyroidectomy for screened at risk subjects.
article lists the genes involved in the various MEN syndromes. Most cases of MEN2 derive from a variation in the RET proto-oncogene
, and are specific for cells of neural crest origin.
The protein produced by the RET gene plays an important role in the TGF-beta (transforming growth factor beta) signaling system. Because the TGF-beta system operates in numerous tissues throughout the body, variations in the RET gene can have effects in numerous tissues throughout the body.
MEN2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants. OMIM # lists the syndromes associated with the RET gene.
When inherited, multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant pattern, which means affected people have one affected parent, and possibly-affected siblings and children. Some cases, however, result from spontaneous new mutations in the RET gene. These cases occur in people with no family history of the disorder. In MEN2B, for example, about half of all cases arise as spontaneous new mutations.
, and medullary thyroid carcinoma.
MEN2A is additionally characterized by the presence of parathyroid hyperplasia or tumor.
MEN2B is additionally characterized by the presence of mucocutaneous neuroma, gastrointestinal symptoms (e.g. constipation
and flatulence
), and muscular hypotonia.
MEN2B can present with a Marfanoid
habitus.
Endocrine system
In physiology, the endocrine system is a system of glands, each of which secretes a type of hormone directly into the bloodstream to regulate the body. The endocrine system is in contrast to the exocrine system, which secretes its chemicals using ducts. It derives from the Greek words "endo"...
. The tumors may be benign
Benign
A benign tumor is a tumor that lacks the ability to metastasize. Common examples of benign tumors include moles and uterine fibroids.The term "benign" implies a mild and nonprogressive disease. Indeed, many kinds of benign tumors are harmless to human health...
or malignant (cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
). They generally occur in endocrine organs (e.g. thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
, parathyroid, and adrenals
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
), but may also occur in endocrine tissues of organs not classically thought of as endocrine.
MEN2 is a sub-type of MEN (multiple endocrine neoplasia
Multiple endocrine neoplasia
The term multiple endocrine neoplasia encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign...
) and itself has sub-types, as discussed below.
Classification
Before gene testing was available, the type and location of tumors determined which type of MEN2 a person had. Gene testing now allows a diagnosis before tumors or symptoms develop.A table in the multiple endocrine neoplasia
Multiple endocrine neoplasia
The term multiple endocrine neoplasia encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign...
article compares the various MEN syndromes. MEN2 and MEN1 are distinct conditions, despite their similar names. MEN2 includes MEN2A, MEN2B
Multiple Mucosal Neuromata
Multiple endocrine neoplasia type 3 is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands...
and familial medullary thyroid cancer.
The common feature among the three sub-types of MEN2 is a high propensity to develop medullary thyroid carcinoma.
Presentation
MEN2 can present with a sign or symptom related to a tumor or, in the case of multiple endocrine neoplasia type 2bMultiple endocrine neoplasia type 2b
Multiple endocrine neoplasia type 3 is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands...
, with characteristic musculoskeletal and/or lip and/or gastrointestinal findings.
Medullary thyroid carcinoma (MTC) represent the most frequent initial diagnosis. Occasionally pheochromocytoma
Pheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
and primary hyperparathyroidism
Primary hyperparathyroidism
Primary hyperparathyroidism causes hypercalcemia through the excessive secretion of parathyroid hormone , usually by an adenoma of the parathyroid glands.-Epidemiology:...
may be the initial diagnosis.
In MEN2A primary hyperparathyroidism occurs in only 10%-30% and is usually diagnosed after the third decade of life. It occur in children but this is rare. It may be the sole clinical manifestation of this syndrome but this is unusual.
MEN2A associates medullary thyroid carcinoma with pheochromocytoma in about 20-50% of cases and with primary hyperparathyroidism in 5-20% of cases.
MEN2B associates medullary thyroid carcinoma with pheochromocytoma in 50% of cases, with marfanoid habitus and with mucosal and digestive neurofibromatosis
Neurofibromatosis
Neurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...
.
In familial isolated medullary thyroid carcinoma the other components of the disease are absent.
Management
Management of MEN2 patients includes thyroidectomy including cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved and selective resection of pathologic parathyroid glands for primary hyperparathyroidism.Familial genetic screening is recommended to identify at risk subjects who will develop the disease, permitting early management by performing prophylactic thyroidectomy, giving them the best chance of cure.
Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC indicating the necessity of a complete thyroid surgery for index cases with MTC and the early thyroidectomy for screened at risk subjects.
Causes
The table in the multiple endocrine neoplasiaMultiple endocrine neoplasia
The term multiple endocrine neoplasia encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign...
article lists the genes involved in the various MEN syndromes. Most cases of MEN2 derive from a variation in the RET proto-oncogene
RET proto-oncogene
The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....
, and are specific for cells of neural crest origin.
The protein produced by the RET gene plays an important role in the TGF-beta (transforming growth factor beta) signaling system. Because the TGF-beta system operates in numerous tissues throughout the body, variations in the RET gene can have effects in numerous tissues throughout the body.
MEN2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants. OMIM # lists the syndromes associated with the RET gene.
Genetics
Differences in presentation
As noted, all types of MEN2 include pheochromocytomaPheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
, and medullary thyroid carcinoma.
MEN2A is additionally characterized by the presence of parathyroid hyperplasia or tumor.
MEN2B is additionally characterized by the presence of mucocutaneous neuroma, gastrointestinal symptoms (e.g. constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
and flatulence
Flatulence
Flatulence is the expulsion through the rectum of a mixture of gases that are byproducts of the digestion process of mammals and other animals. The medical term for the mixture of gases is flatus, informally known as a fart, or simply gas...
), and muscular hypotonia.
MEN2B can present with a Marfanoid
Marfanoid
Marfanoid is a term used to describe a constellation of findings including long limbs, arachnodactyly and hyperlaxity.Associated conditions include:* Marfan syndrome...
habitus.
See also
- Multiple endocrine neoplasiaMultiple endocrine neoplasiaThe term multiple endocrine neoplasia encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign...
- Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1 or Wermer's syndrome is part of a group of disorders that affect the endocrine system.-Explanation:...
- Multiple endocrine neoplasia type 2bMultiple endocrine neoplasia type 2bMultiple endocrine neoplasia type 3 is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands...
- Multiple mucosal neuromataMultiple Mucosal NeuromataMultiple endocrine neoplasia type 3 is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands...